U.S. patent number 10,307,403 [Application Number 16/202,487] was granted by the patent office on 2019-06-04 for polymorphic forms and process.
This patent grant is currently assigned to GALECTO BIOTECH AB. The grantee listed for this patent is GALECTO BIOTECH AB. Invention is credited to Lise Gravelle, Anders Pedersen.
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United States Patent |
10,307,403 |
Gravelle , et al. |
June 4, 2019 |
Polymorphic forms and process
Abstract
The present invention relates to a polymorph of a compound of
formula (I) ##STR00001## This polymorph is particularly suitable in
treating IPF by pulmonary administration.
Inventors: |
Gravelle; Lise (Laval,
CA), Pedersen; Anders (Lyngby, DK) |
Applicant: |
Name |
City |
State |
Country |
Type |
GALECTO BIOTECH AB |
Copenhagen |
N/A |
DK |
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Assignee: |
GALECTO BIOTECH AB (Copenhagen,
DK)
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Family
ID: |
54979474 |
Appl.
No.: |
16/202,487 |
Filed: |
November 28, 2018 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190117627 A1 |
Apr 25, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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16062206 |
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PCT/EP2016/081432 |
Dec 16, 2016 |
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Foreign Application Priority Data
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Dec 18, 2015 [EP] |
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15201223 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
9/00 (20180101); C07H 1/00 (20130101); C07H
19/056 (20130101); A61K 31/35 (20130101); A61P
11/00 (20180101); A61K 31/4192 (20130101); A61K
31/70 (20130101); A61K 9/0073 (20130101) |
Current International
Class: |
A61K
31/4192 (20060101); A61P 9/00 (20060101); A61P
11/00 (20060101); C07H 19/056 (20060101); A61K
9/00 (20060101); A61K 31/70 (20060101); A61K
31/35 (20060101); C07H 1/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Alison C. Mackinnon et al: "Regulation of Transforming Growth
Factor-[beta]1-driven Lung Fibrosis by Galectin-3", American
Journal of Respiratory and Critical Care Medicine, vol. 185, No. 5,
Mar. 1, 2012 (Mar. 1, 2012), pp. 537-546. cited by applicant .
International Search Report and Written Opinion dated Jan. 26, 2017
of corresponding application No. PCT/EP2016/081432, 9 pgs. cited by
applicant .
U.S. Office Action dated Feb. 5, 2019, in connection with
corresponding U.S. Appl. No. 16/062,206 (13 pgs.). cited by
applicant.
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Primary Examiner: Saeed; Kamal A
Attorney, Agent or Firm: Maier & Maier, PLLC
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser.
No. 16/062,206, filed Jun. 14, 2018, which is a national stage
application of International Application No. PCT/EP2016/081432,
filed Dec. 16, 2016, which claims priority to European Patent
Application No. 15201223.3, filed Dec. 18, 2015, the entire
contents of which are incorporated herein by reference.
Claims
We claim:
1. A polymorph of a compound of formula (I) ##STR00006## wherein
the polymorph is
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside and wherein: the polymorph
has a polymorphic form 1 as identified in the following XRPD
diffractogram peak list: TABLE-US-00007 No. Pos. [.degree.2Th.]
Rel. Int. [%] 1 7.1269 77.72 2 7.5067 56 3 10.125 36.86 4 14.3791
32.28 5 15.0846 18.59 6 15.8201 35.78 7 16.7088 78.1 8 18.6001
21.29 9 19.7777 100 10 20.3353 57.04 11 21.7744 79.92 12 22.6053
35.8 13 23.4305 45.78 14 24.3658 51.03 15 25.8091 54.36 16 26.7046
25.38 17 29.028 16.19 18 30.2989 28.02 19 32.2693 14.86 20 33.5132
11.55 21 34.6078 11.54 22 35.8435 9.6 23 44.6257 22.73;
or the polymorph has a polymorphic form 1 as identified in the XRPD
diffractogram in FIG. 1.
2. The polymorph of claim 1, wherein the polymorph is a
hydrate.
3. The polymorph of claim 2, wherein the hydrate contains 3-5% by
weight water.
4. The polymorph of claim 1, wherein the polymorph is
micronized.
5. The polymorph of claim 4, wherein the polymorph is micronized to
a size that can reach the bronchioles and/or the alveoli of the
human.
6. A pharmaceutical composition comprising the polymorph of claim
1, and optionally a pharmaceutically acceptable additive.
7. A process of making the polymorph of claim 1 comprising:
suspending or dissolving
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside in an organic solvent; and
then making polymorphic form 1 by temperature cycling, crash
cooling, evaporation, or a combination thereof.
8. A method for treatment of pulmonary fibrosis in a human
comprising administering to the lung tissue of the human an amount
of the polymorph of claim 1 effective to treat said pulmonary
fibrosis.
9. The method of claim 8, wherein the administration is carried out
by a dry powder inhaler.
10. The method of claim 9, wherein the administration is carried
out by a monodose dry powder inhaler.
11. The method of claim 8, wherein the polymorph is administered to
the bronchioles and/or the alveoli of the human.
12. The method of claim 8, wherein the amount is a once daily
amount from 0.15 mg to 50 mg.
13. The method of claim 12, wherein the amount is a once daily
amount selected from the group consisting of: 0.15 mg to 0.50 mg,
0.50 mg to 0.75 mg, 0.75 mg to 1.25 mg, 1.25 mg to 1.5 mg, 1.5 mg
to 1.75 mg, 1.75 mg to 2 mg, 2 mg to 2.25 mg, 2.25 mg to 2.5 mg,
2.5 mg to 2.75 mg, 2.75 mg to 3 mg, 3 mg to 5 mg, 5 mg to 7 mg, 7
mg to 8 mg, 8 mg to 10 mg, 10 mg to 20 mg and 20 mg to 50 mg.
14. A method for treatment of pulmonary fibrosis in a human
comprising administering to the lung tissue of the human an amount
of the polymorph of claim 2 effective to treat said pulmonary
fibrosis.
15. A method for treatment of pulmonary fibrosis in a human
comprising administering to the lung tissue of the human an amount
of the polymorph of claim 3 effective to treat said pulmonary
fibrosis.
16. A method for treatment of pulmonary fibrosis in a human
comprising administering to the lung tissue of the human an amount
of the polymorph of claim 4 effective to treat said pulmonary
fibrosis.
17. A method for treatment of pulmonary fibrosis in a human
comprising administering to the lung tissue of the human an amount
of the polymorph of claim 5 effective to treat said pulmonary
fibrosis.
Description
TECHNICAL FIELD
The present invention relates to a polymorph of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside.
BACKGROUND ART
Idiopathic pulmonary fibrosis (IPF) represents a massive worldwide
health burden. It is a chronic condition of unknown etiology in
which repeated acute lung injury causes progressive fibrosis
resulting in destruction of lung architecture, deteriorating lung
function with consequent respiratory failure and death. Although
idiopathic pulmonary fibrosis (IPF) is the archetypal and most
common cause of lung fibrosis, numerous respiratory diseases can
progress to pulmonary fibrosis, and this usually signifies a worse
prognosis. The median time to death from diagnosis is 2.5 years and
the incidence and prevalence of IPF continues to rise. It remains
one of the few respiratory conditions for which there are no
effective therapies, and there are no reliable biomarkers to
predict disease progression. The mechanisms resulting in pulmonary
fibrosis are unclear but centre around aberrant wound healing as a
consequence of repetitive epithelial injury from an as yet unknown
cause. IPF is characterized by fibroblastic foci containing
fibroblasts/myofibroblasts which show increased activation response
to fibrogenic cytokines such as transforming growth factor-.beta.
(TGF-.beta.1). There is a big unmet need for drugs for treatment of
Idiopathic pulmonary fibrosis.
SUMMARY OF THE DISCLOSURE
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside is a white to off white
crystalline solid where 6 polymorphs as well as an amorphous form
have been identified.
In one aspect, the present invention relates to a polymorph of a
compound of formula (I)
##STR00002## The compound of formula (I) is
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside and has the polymorphic Form
1 as identified in the XRPD diffractogram peak list
TABLE-US-00001 No. Pos. [.degree.2Th.] Rel. Int. [%] 1 7.1269 77.72
2 7.5067 56 3 10.125 36.86 4 14.3791 32.28 5 15.0846 18.59 6
15.8201 35.78 7 16.7088 78.1 8 18.6001 21.29 9 19.7777 100 10
20.3353 57.04 11 21.7744 79.92 12 22.6053 35.8 13 23.4305 45.78 14
24.3658 51.03 15 25.8091 54.36 16 26.7046 25.38 17 29.028 16.19 18
30.2989 28.02 19 32.2693 14.86 20 33.5132 11.55 21 34.6078 11.54 22
35.8435 9.6 23 44.6257 22.73
Moreover, the polymorphic form 1 of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside can be identified in the
XRPD diffractogram in FIG. 1 or FIG. 2.
In a further aspect of the present invention a polymorph of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside is designated Form 1 and is
a hydrated crystalline form. The hydrate is not stoichiometric but
rather a channel hydrate. Form 1 is dried upon synthesis, however
it will pick up moisture and equilibrate at around 3-5% water
content. Form 1 is stable and does not convert to the other forms
over time.
Furthermore, form 1 can be further processed by micronization,
which is particularly useful when preparing a composition for use
in dry powder delivery to the lungs, in particular the narrowest
parts of the lung tissue that is the bronchioles and the
alveoli.
In a further aspect, the present invention relates to a
pharmaceutical composition comprising a polymorph of the present
invention, and optionally a pharmaceutically acceptable
additive.
In a still further aspect the present invention relates to a
process of making a polymorph of the present invention comprising
the steps of suspending or dissolving
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside in an organic solvent and
then making form 1 by temperature cycling, crash cooling or
evaporation, or a combination thereof.
In a further aspect, the present invention relates to a process for
preparing an amorphous form of a compound of formula (I)
##STR00003## comprising the steps of spray drying a solution of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside in an organic solvent and
collecting the amorphous compound of formula (I).
In a still further aspect the present invention relates to a method
for treatment of pulmonary fibrosis in a human comprising
administering to the narrowest parts of the lung tissue of the
human an amount of a polymorph of the present invention effective
to treat said pulmonary fibrosis.
BRIEF DESCRIPTION OF FIGURES
FIG. 1: XRPD Diffractogram for Form 1.
FIG. 2: XRPD Diffractogram for Form 1.
FIG. 3: XRPD Diffractogram for Form 2.
FIG. 4: XRPD Diffractogram for Form 3.
FIG. 5: XRPD Diffractogram for Form 4.
FIG. 6: XRPD Diffractogram for Form 5.
FIG. 7: XRPD Diffractogram for Form 6.
FIG. 8: XRPD Diffractogram for micronized form 1.
FIG. 9: XRPD Diffractogram for micronized form 1.
FIG. 10: XRPD Diffractogram for micronized form 1.
DETAILED DESCRIPTION
The compound of formula (I) has the chemical name (IUPAC)
3,3'-Dideoxy-3,3'-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sulf-
anediyl-di-.beta.-D-galactopyranoside.
The compound of formula (I) may be prepared as described in
US2014/0121179 or WO2014/067986, wherein an amorphous solid is
produced.
The present invention concerns a polymorph of a compound of formula
(I)
##STR00004##
In one embodiment, the compound of formula (I) is
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside and has the polymorphic form
1 as identified in the XRPD diffractogram peak list
TABLE-US-00002 No. Pos. [.degree.2Th.] Rel. Int. [%] 1 7.1269 77.72
2 7.5067 56 3 10.125 36.86 4 14.3791 32.28 5 15.0846 18.59 6
15.8201 35.78 7 16.7088 78.1 8 18.6001 21.29 9 19.7777 100 10
20.3353 57.04 11 21.7744 79.92 12 22.6053 35.8 13 23.4305 45.78 14
24.3658 51.03 15 25.8091 54.36 16 26.7046 25.38 17 29.028 16.19 18
30.2989 28.02 19 32.2693 14.86 20 33.5132 11.55 21 34.6078 11.54 22
35.8435 9.6 23 44.6257 22.73
The compound of formula (I) is
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside and has the polymorphic form
1 as identified in the XRPD diffractogram in FIG. 1.
The compound of formula (I) is
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside and has the polymorphic form
1 as identified in the XRPD diffractogram in FIG. 2.
In a further embodiment, the compound of formula (I) is
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside as a hydrate.
In a still further embodiment the
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside hydrate contains 3-5% water
(weight %).
In a further embodiment, the compound of formula (I) is
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside selected from Form 2, 3, 4,
5 or 6 as identified in the XRPD diffractogram in FIGS. 3-7,
respectively. Form 5 (FIG. 6) is particularly interesting as it is
stable and suitable for use in a nebulizer for pulmonary
administration.
In a still further embodiment the polymorph is a dry powder, such
as micronized polymorph. Such as, micronized Form 1.
In a further embodiment, the polymorph, such as Form 1, is
micronized to a size that can reach the narrowest parts of the lung
tissue of the human, such as the bronchioles and the alveoli.
In a further aspect, the present invention relates to a polymorph
of the present invention for use in a method for treatment of
pulmonary fibrosis in a human. Preferably the polymorph for use in
treatment of pulmonary fibrosis is selected from Form 1 and 5,
typically Form 1.
In a still further aspect the present invention relates to a
pharmaceutical composition comprising the polymorph of the present
invention, and optionally a pharmaceutically acceptable additive.
Typically, the polymorph used in the composition is Form 1 as a dry
powder, such as micronized dry powder neat or mixed with an
additive, such as lactose.
In a further aspect, the present invention relates to a DPI
comprising a polymorph of the present invention, such as form 1. In
an embodiment, the polymorph, such as Form 1, is micronized to a
size that can reach the narrowest parts of the lung tissue of the
human, such as the bronchioles and the alveoli. In a further
embodiment, the DPI comprising the polymorph of form 1 for use in a
method for treatment of pulmonary fibrosis in a human. In a still
further embodiment the DPI is a single or multiple dose DPI
inhaler. In one particular embodiment, the dry powder inhaler is
RS01 Monodose Dry Powder Inhaler (Plastiape).
Another aspect concerns a process of making a polymorph Form 1 of
the present invention comprising the steps of suspending or
dissolving
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside in an organic solvent and
then making Form 1 by temperature cycling, crash cooling or
evaporation, or a combination thereof. The compound
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside used as starting material
may be amorphous or any crystalline form since the above process
will generate Form 1. In a further embodiment, the organic solvent
is selected from methanol, ethanol, acetone, acetonitrile, toluene,
tert-butylmethylether, hexane and diisopropylether as well as
mixtures thereof.
A further aspect concerns a process for preparing an amorphous form
of a compound of formula (I)
##STR00005## comprising the steps of spray drying a solution of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside in an organic solvent and
collecting the amorphous compound of formula (I). The compound
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside used as starting material
may be any crystalline form since the above process will generate
the amorphous form from the dissolved compound. In a further
embodiment the organic solvent is selected from a mixture of
acetone and water, such as acetone:water 50:50 to 80:20. In a still
further embodiment the dissolved compound is introduced in a drying
chamber at a feed concentration of from 0.5% to 20% by weight, such
as from 1-10% weight, such as from 2-7% weight, e.g. about 3.5%
weight. In a further embodiment, the drying chamber has a drying
gas temperature at the inlet of from 120-160.degree. C., such as
from 140-150.degree. C., e.g. about 144.degree. C. In a still
further embodiment the drying chamber has a drying gas temperature
at the outlet of from 60-90.degree. C., such as from 70-80.degree.
C., e.g. about 75.degree. C. In a further embodiment drying time in
the drying chamber is from 30-120 minutes, such as from 45-75
minutes, e.g. about 50 minutes.
In a still further aspect the present invention relates to a method
for treatment of pulmonary fibrosis in a human comprising
administering to the narrowest parts of the lung tissue of the
human an amount of a polymorph of the present invention, such as
Form 1 or 5, effective to treat said pulmonary fibrosis.
In a further embodiment, the pulmonary fibrosis is Idiopathic
pulmonary fibrosis (IPF).
In a further embodiment, the administration is carried out by a dry
powder inhaler. Typically, a single or multiple dose DPI inhaler is
used. In one particular embodiment, the dry powder inhaler is RS01
Monodose Dry Powder Inhaler (Plastiape).
When a polymorph of the compound of formula (I), typically Form 1,
is formulated as a dry powder it may be present in a suitable
particle size selected from a mean mass aerodynamic diameter (MMAD)
between 0.1 and 20 .mu.m, such as a MMAD between 0.5 and 10 .mu.m,
such as between 1 and 5 .mu.m, typically between 2 and 3 .mu.m. The
selected ranges do not exclude the presence of particles sizes
outside these ranges, but the selected ranges are those that
provide the desired effect as described herein.
In a still further embodiment the narrowest parts of the lung
tissue are the bronchioles and the alveoli.
In a further embodiment the once daily amount is from 0.15 mg to 50
mg, such as 0.15 mg to 0.50 mg, 0.50 mg to 0.75 mg, 0.75 mg to 1.25
mg, 1.25 mg to 1.5 mg, 1.5 mg to 1.75 mg, 1.75 mg to 2 mg, 2 mg to
2.25 mg, 2.25 mg to 2.5 mg, 2.5 mg to 2.75 mg, 2.75 mg to 3 mg, 3
mg to 5 mg, 5 mg to 7 mg, 7 mg to 8 mg, 8 mg to 10 mg, 10 mg to 20
mg and 20 mg to 50 mg. The once daily amount form 1.5 mg to 20 mg
result in a concentration of the active compound of formula (I) in
BAL fluids or macrophages or both of from 1 nM to 500 .mu.M. In
particular, the once daily amount form 1.5 mg to 20 mg result in a
concentration of the active compound of formula (I) in BAL fluids
or macrophages or both of from 1 nM to 100 .mu.M. More preferred
concentrations of from 10 nM to 10 .mu.M or more preferred 100 nM
to 1 .mu.M can be provided with once daily amount from 1 mg to 10
mg, such as from 1 mg to 3 mg or 3 mg to 10 mg, e.g. 1 mg to 3 mg.
Other preferred concentrations of the active compound of formula
(I) in BAL fluids is from 10 nM to 10 .mu.M, such as from 100 nM to
10 .mu.M, typically from 500 nM to 10 .mu.M, such as up to 4 .mu.M.
Other preferred concentrations of the active compound of formula
(I) in macrophages is from 1 .mu.M to 500 .mu.M, such as from 10
.mu.M to 250 .mu.M, typically from 50 .mu.M to 200 .mu.M, such as
up to 100 .mu.M.
In a still further embodiment the treatment is chronic
treatment.
The term "treatment" and "treating" as used herein means the
management and care of a patient for the purpose of combating a
condition, such as a disease or a disorder. The term is intended to
include the full spectrum of treatments for a given condition from
which the patient is suffering, such as administration of the
active compound to alleviate the symptoms or complications, to
delay the progression of the disease, disorder or condition, to
alleviate or relief the symptoms and complications, and/or to cure
or eliminate the disease, disorder or condition as well as to
prevent the condition, wherein prevention is to be understood as
the management and care of a patient for the purpose of combating
the disease, condition, or disorder and includes the administration
of the active compounds to prevent the onset of the symptoms or
complications. The treatment is performed in a chronic way. The
patient to be treated is a human subject diagnosed with pulmonary
fibrosis or other types of lung fibrosis.
The term "an amount effective to treat pulmonary fibrosis" of a
compound of formula (I) of the present invention as used herein
means an amount sufficient to cure, alleviate or partially arrest
the clinical manifestations of pulmonary fibrosis and its
complications. Effective amounts for each purpose will depend on
the severity of the disease or injury as well as the weight and
general state of the subject. It will be understood that
determining an appropriate dosage may be achieved using routine
experimentation, by constructing a matrix of values and testing
different points in the matrix, which is all within the ordinary
skills of a trained physician or veterinary.
As used herein "pharmaceutically acceptable additive" is intended
without limitation to include carriers, excipients, diluents,
adjuvant, colorings, aroma, preservatives etc. that the skilled
person would consider using when formulating a compound of the
present invention in order to make a pharmaceutical
composition.
The adjuvants, diluents, excipients and/or carriers that may be
used in the composition of the invention must be pharmaceutically
acceptable in the sense of being compatible with the compound of
formula (I) and the other ingredients of the pharmaceutical
composition, and not deleterious to the recipient thereof. It is
preferred that the compositions shall not contain any material that
may cause an adverse reaction, such as an allergic reaction. The
adjuvants, diluents, excipients and carriers that may be used in
the pharmaceutical composition of the invention are well known to a
person within the art.
As mentioned above, the compositions and particularly
pharmaceutical compositions as herein disclosed may, in addition to
the compounds herein disclosed, further comprise at least one
pharmaceutically acceptable adjuvant, diluent, excipient and/or
carrier. In one embodiment the pharmaceutical composition contains
neat compound of formula I. In some embodiments, the pharmaceutical
compositions comprise from 1 to 99 weight % of said at least one
pharmaceutically acceptable adjuvant, diluent, excipient and/or
carrier and from 1 to 99 weight % of a compound of formula I as
herein disclosed. The combined amount of the active ingredient and
of the pharmaceutically acceptable adjuvant, diluent, excipient
and/or carrier may not constitute more than 100% by weight (100%
w/w) of the composition, particularly the pharmaceutical
composition. In accordance with the present invention the
pharmaceutical composition may consist of neat compound of formula
I (that is 100% w/w compound of formula I) or contain a 1-90% w/w,
such as 2-20% w/w, for instance a 3% w/w blend of the compound of
formula I or a 10% w/w blend of the compound of formula I.
Typically, the 3% w/w blend is a pharmaceutical composition
containing 3% w/w compound of formula I and 97% w/w lactose
carrier. Typically, the 10% w/w blend is a pharmaceutical
composition containing 10% w/w compound of formula I and 90% w/w
lactose carrier.
To the person skilled in the art it is well known that particles
with a mean mass aerodynamic diameter (MMAD) between 0.1 and 20
.mu.m (micro meter) have an increased probability of depositing in
the terminal bronchial and alveolar regions. This particle size
range is ideal for many indications in pulmonary drug delivery,
since a portion of the material will still deposit in the upper
airways as well. (Cf. Controlled Pulmonary Drug Delivery, Smith and
Hickey, Editors, Springer 2011, chapter 13).
In accordance with Controlled Pulmonary Drug Delivery, Smith and
Hickey, Editors, Springer 2011 in particular chapters 13, 14 and 15
the skilled person will know how to formulate compounds, such as
the compound of formula (I) for pulmonary drug delivery.
Dry powder inhalers (DPI), are well known for dispensing medicament
to the lungs of a patient. Preferred DPIs for use in the present
invention is a monodose dry powder inhaler from Plastiape (HQ,
Osnago, Italy), in particular the RS01 Monodose Dry Powder
Inhaler.
Current DPI designs include pre-metered and device-metered
inhalers, both of which can be driven by patient inspiration alone
or with power-assistance of some type. Pre-metered DPIs contain
previously measured doses or dose fractions in some type of units
(e.g., single or multiple presentations in blisters, capsules, or
other cavities) that are subsequently inserted into the device
during manufacture or by the patient before use. Thereafter, the
dose may be inhaled directly from the pre-metered unit or it may be
transferred to a chamber before being inhaled by the patient.
Device-metered DPIs have an internal reservoir containing
sufficient formulation for multiple doses that are metered by the
device itself during actuation by the patient. The wide array of
DPI designs, many with characteristics unique to the design, will
present challenges in developing information in support of an
application. Regardless of the DPI design, the most crucial
attributes are the reproducibility of the dose and particle size
distribution. Maintaining these qualities through the expiration
dating period and ensuring the functionality of the device through
its lifetime under patient-use conditions will probably present the
most formidable challenge.
Pressurized Metered-Dose Inhalers (pMDI) may also be suitable
delivery devices for the present compound of formula (I) and are
described in Controlled Pulmonary Drug Delivery, Smith and Hickey,
Editors, Springer 2011, chapter 8.
Several types of non-aerosol, breath actuated dry powder inhalers
have therefore been provided. For example, U.S. Pat. No. 5,503,144
to Bacon, shows a breath-actuated dry-powder inhaler. The device
includes a dry powder reservoir for containing a dry powdered
medicament, a metering chamber for removal of the powdered
medicament from the reservoir in discrete amounts, and an air inlet
for entraining the removed powdered medicament through a mouthpiece
upon patient inhalation.
U.S. Pat. No. 5,458,135 discloses a method and apparatus for
producing an aerosolized dose of a medicament for subsequent
inhalation by a patient. The method comprises first dispersing a
preselected amount of the medicament in a predetermined volume of
gas, usually air. The dispersion may be formed from a liquid or a
dry powder. The method relies on flowing substantially the entire
aerosolized dose into a chamber that is initially filled with air
and open through a mouthpiece to the ambient. After the aerosolized
medicament, has been transferred to the chamber, the patient will
inhale the entire dose in a single breath.
U.S. Pat. No. 6,065,472 discloses a powder inhalation device
comprising a housing containing a pharmacologically active
compound, a conduit with an outlet extending into the housing
through which a user can inhale to create an airflow through the
conduit, a dosing unit for delivering a dose of the compound to the
conduit and baffles arranged within the said conduit to aid
disintegration of powder agglomerates entrained in said
airflow.
Regardless of whether an aerosol or non-aerosol inhaler is used, it
is of utmost importance that particles of the dispensed dry powder
medicament be small enough to ensure the adequate penetration of
the medicament into the bronchial region of a patient's lungs
during inhalation. However, because the dry powder medicament is
composed of very small particles, and often provided in a
composition including a carrier such as lactose, non-defined
agglomerates or aggregates of the medicament form at random prior
to being dispensed. It has therefore been found preferably to
provide breath-actuated dry powder inhalers with means for breaking
down the agglomerates of medicament or medicament and carrier
before inhalation of the medicament.
Boehringer Ingelheim provided a new technology in 1997 named
Raspimat which is a mechanical nebulizer of the soft mist inhaler
type. This mechanical nebulizer is operated by hand without any
need for a gas propellant and no need for electrical power. Another
mechanical nebulizer is a human powered nebulizer developed by a
team from Marquette University. This nebulizer can by operated by
an electrical compressor, but it is also suitable for simple
mechanical pumps in order to provide a mist into the lungs of
patients. Further nebulizers of the electrical type are ultrasonic
nebulizers based on the vibrating mesh technology developed by
inter alia PARI, Respironics, Omron, Beurer, Aerogen, or ultrasonic
nebulizers based on an electronic oscillator that generate a high
frequency ultrasonic wave developed by inter alia Omron and Beurer.
A further electrical nebulizer is a jet nebulizer also known as
atomizers.
In a further embodiment, the nebulizer is selected from a
mechanical nebulizer, such as a soft mist inhaler or a human
powered nebulizer. In another embodiment, the nebulizer is selected
from an electrical nebulizer, such as a nebulizer based on
ultrasonic vibrating mesh technology, a jet nebulizer, or an
ultrasonic wave nebulizer. Particular suitable nebulizers are based
on vibrating mesh technology such as eFlow from PARI. When treating
pulmonary fibrosis, in particular IPF, it is important to obtain
adequately high local concentrations of the therapeutic in the
narrowest parts of the lung tissue, including the bronchioles and
the alveoli. Further, it is important that the therapeutic obtains
an adequate residence time at the site of action in the lung
tissue. However, cough is a central symptom for patients with
pulmonary fibrosis and in particular IPF--a symptom that is likely
to be aggravated if an irritant is introduced into the lung.
However, delivering the compound using a nebulizer, such as an
electronic nebulizer, is particularly beneficial, since it allows
delivery of the compound to the smallest compartments in the lung,
without causing any irritation in the lung. Such relevant nebulizer
systems are described in published patent applications
US20040089295, US20050056274, US20060054166, US20060097068,
US20060102172, US20080060640, US20110155768, and US20120167877, all
of which are incorporated herein by reference. Other suitable
nebulizers are Tyvaso inhalation system from United Therapeutics,
Allera nebulizer system from Gilead, Bronchitol inhaler from
Pharmaxis, Diskhaler from GSK, jet and ultrasonic nebulizers from
Actelion and Profile Pharma.
Further embodiments of the process are described in the
experimental section herein, and each individual process as well as
each starting material constitutes embodiments that may form part
of embodiments.
The above embodiments should be seen as referring to any one of the
aspects (such as `method for treatment`, `pharmaceutical
composition`, `compound for use as a medicament`, or `compound for
use in a method`) described herein as well as any one of the
embodiments described herein unless it is specified that an
embodiment relates to a certain aspect or aspects of the present
invention.
All references, including publications, patent applications and
patents, cited herein are hereby incorporated by reference to the
same extent as if each reference was individually and specifically
indicated to be incorporated by reference and was set forth in its
entirety herein.
All headings and sub-headings are used herein for convenience only
and should not be construed as limiting the invention in any
way.
Any combination of the above-described elements in all possible
variations thereof is encompassed by the invention unless otherwise
indicated herein or otherwise clearly contradicted by context.
The terms "a" and "an" and "the" and similar referents as used in
the context of describing the invention are to be construed to
cover both the singular and the plural, unless otherwise indicated
herein or clearly contradicted by context.
Recitation of ranges of values herein are merely intended to serve
as a shorthand method of referring individually to each separate
value falling within the range, unless otherwise indicated herein,
and each separate value is incorporated into the specification as
if it were individually recited herein. Unless otherwise stated,
all exact values provided herein are representative of
corresponding approximate values (e.g., all exact exemplary values
provided with respect to a particular factor or measurement can be
considered to also pro-vide a corresponding approximate
measurement, modified by "about," where appropriate).
All methods described herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context.
The use of any and all examples, or exemplary language (e.g., "such
as") provided herein, is intended merely to better illuminate the
invention and does not pose a limitation on the scope of the
invention unless otherwise indicated. No language in the
specification should be construed as indicating any element is
essential to the practice of the invention unless as much is
explicitly stated.
The citation and incorporation of patent documents herein is done
for convenience only and does not reflect any view of the validity,
patentability and/or enforceability of such patent documents.
The description herein of any aspect or embodiment of the invention
using terms such as "comprising", "having", "including" or
"containing" with reference to an element or elements is intended
to provide support for a similar aspect or embodiment of the
invention that "consists of", "consists essentially of", or
"substantially comprises" that particular element or elements,
unless otherwise stated or clearly contradicted by context (e.g., a
composition described herein as comprising a particular element
should be understood as also describing a composition consisting of
that element, unless otherwise stated or clearly contradicted by
context).
This invention includes all modifications and equivalents of the
subject matter recited in the aspects or claims presented herein to
the maximum extent permitted by applicable law.
The present invention is further illustrated by the following
examples that, however, are not to be construed as limiting the
scope of protection. The features disclosed in the foregoing
description and in the following examples may, both separately and
in any combination thereof, be material for realizing the invention
in diverse forms thereof.
Experimental
The current process to manufacture polymorphic Form 1 of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside involves a final
purification step with either trituration or crystallization from
ethanol to produce Form 1.
Form 1 of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl-
]-1,1'-sulfanediyl-di-.beta.-D-galactopyranoside can be prepared
via trituration following the steps below: Suspend crystalline or
amorphous
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside in ethanol (3.6 vol). Warm
the suspension to 70.degree. C..+-.5.degree. C. Stir the mixture
for 30 min at 70.degree. C..+-.5.degree. C. Allow the mixture to
cool to 20.degree. C..+-.5.degree. C. Filter and rinse with eight
portions of ethanol (8.times.0.75 vol). Draw air through the filter
cake for a minimum of 15 min. Dry the filter cake in vacuo at
70.degree. C. with an air bleed to provide purified
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside. Form 1 of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di(.beta.-D-galactopyranoside can be prepared via
crystallization following the steps below: Combine crystalline or
amorphous
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside with ethanol (3.5 vol) and
water (1.5 vol). Heat the mixture to 45-50.degree. C. over 60 to 90
minutes. Clarify the mixture through a 1 .mu.m filter at
18-23.degree. C. Adjust the temperature to 30-40.degree. C. (target
38.degree. C.) and concentration the mixture under reduced pressure
to about 5 vol. Add ethanol (10 vol) to the mixture at a
temperature of 30-40.degree. C. (target 38.degree. C.).
Re-concentrate the mixture to about 5 vol. Heat the mixture to
65-75.degree. C. (target 70.degree. C.) and stir for 30-40 minutes.
Cool the mixture to 18-23.degree. C. (target 20.degree. C.) over at
least 90 minutes. Stir the mixture for at least 45 minutes at
18-23.degree. C. (target 20.degree. C.). Filter and wash the filter
cake with ethanol at 18-23.degree. C. (target 20.degree. C.). Dry
the filter cake at 18-23.degree. C. to provide purified
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside.
A polymorph screen was conducted using Form 1 material generated
via trituration as the final purification step. The polymorph
screen results indicated that there are 6 potential polymorphs for
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-3-D-galactopyranoside. Table 2 indicates conditions
that generated each polymorph (Form 1-6).
TABLE-US-00003 TABLE 2 Conditions to Generate 6 Polymorphs of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluoro-
phenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sulfanediyl-di-.beta.-D-galactopyranos-
ide Temperature Crash cool Crash Cool Anti-solvent Solvent cycling
(2.degree. C.) (-20.degree. C.) addition Evaporation Acetone Form 1
Acetone:Water (20%) PLM PLM Form 2 Acetonitrile WD PLM PLM Form 3
Dichloromethane PLM Form 4 Diisopropyl ether Am Form 5
Dimethylacetamide Am Form 6 Dimethylformamide Am PLM No solid
Dimethylsulfoxide WD Frozen Frozen PLM Gum Am Amorphous by PLM
1,4-Dioxane Am Frozen Frozen PLM PLM Crystalline by PLM Ethanol WD
WD Weak data (crystalline) Ethyl acetate WD Gum Gum Hexane Am
Experiment not performed Isopropyl acetate PLM Methanol Methylethyl
ketone W D Methyl isobutyl ketone PLM N-methyl 2-pyrrolidone PLM
Gum 2-Propanol PLM Tert-buytlmethyl ether Am Tetrahydrofuran PLM Am
Toluene Am Water WD Frozen PLM Water:Propylene glycol (75:25) WD
Frozen Water:PEG400:Ethanol WD Frozen Gum (65:25:10)
Form 1 is a hydrated form and can be produced from temperature
cycling, crash cooling and evaporation experiments in 8 different
solvents including methanol, ethanol, acetone, acetonitrile,
toluene, tert-butylmethylether, hexane and diisopropylether. Form 2
is a channel hydrate or hygroscopic form and can be produced from
temperature cycling, crash cooling, anti-solvent addition and
evaporation experiments in 7 different solvents including acetone,
acetone:water (20%), methylethyl ketone, tetrahydrofuran,
dichloromethane, dimethylformamide and dimethylacetamide. Form 3 is
a solvate and can be produced from temperature cycling,
anti-solvent addition and evaporation in 9 different solvents
including dichloromethane, dimethylacetamide, ethyl acetate,
isopropyl acetate, methyl isobutyl ketone, tetrahydrofuran,
acetone, acetone:water (20%) and dimethylacetamide. Form 4 is a
solvate and can be produced from temperature cycling in 2-propanol.
Form 5 is a hydrate and can be produced from temperature cycling in
dimethylsulfoxide, water, water:propylene glycol (75:25) and
water:PEG400:ethanol (65:25:10). Form 6 is a hydrate/solvate and
can be produced from temperature cycling and evaporation
experiments in dimethylformamide and N-methyl-2-pyrrolidone.
3,3'-Dideoxy-3,3'-bis-[4-(3
fluorophenyl)-H-1,2,3-triazol-1-yl)-1H-1,2,3-triazol-yl]-1,1'-sulfanediyl-
-di-.beta.-D-galactopyranoside Form 5 has also been prepared via
microfluidization (wet polishing) using water as an
anti-solvent.
The amorphous form of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside has been prepared through
spray drying from a solution of acetone:water.
To compare in vitro performance of the different forms for use in
inhalation products, an aerodynamic particle size determination
(APSD) was performed via New Generation Impactor (NGI) for Form 5
material produced via microfluidization and the amorphous form
produced via spray drying. These were compared with the APSD
obtained from micronized Form 1 material. For each APSD test, 20 mg
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside was filled into a size 3
HPMC capsule and actuated using a Plastiape Monodose inhaler
device. The NGI results are provided in Table 3 and demonstrate
that all three forms (Form 1, Form 5 and amorphous) have acceptable
in vitro aerosol performance with Fine Particle Fraction (FPF)
above 60% and MMAD values in the respirable range.
TABLE-US-00004 TABLE 3 APSD Results for Form 1, Form 5 and
Amorphous 3,3'-Dideoxy-
3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-
1-yl]-1,1'-sulfanediyl-di-.beta.-D-galactopyranoside Fine Fine Mean
Mass Geometric Particle Particle Aerodynamic Standard Dose Fraction
Diameter Deviation Form (FPD) (FPF) (MMAD) (GSD) Form 1
(micronized) 7.4 mg 77% 2.6 .mu.m 1.8 .mu.m Form 5 7.7 mg 63% 2.3
.mu.m 2.3 .mu.m (microfluidization) Amorphous 11.8 mg 91% 1.7 .mu.m
1.8 .mu.m (Spray Drying)
Micronized Form 1 was placed on stability under ICH conditions and
the results in Table 3A demonstrate that Form 1 is stable both
chemically and physically. There is no increase in impurities and
both the particle size and crystalline form remain unchanged.
TABLE-US-00005 TABLE 3A Stability Results for Micronized Form 1 6
Months 12 Months Test Acceptance Criteria Initial @ 40.degree.
C./75 RH 25.degree. C./60 RH Appearance White to off-white solid
Conforms Conforms Conforms Assay 95.0-105.0% w/w.sup.1 97.9% 97.2%
97.7% Specified DEX283 .ltoreq.1% (a/a) ND ND ND impurities
DEX-IMP-284-A .ltoreq.1% (a/a) ND ND ND DEX-IMP-284-B .ltoreq.1%
(a/a) 0.90% 0.89% 0.89% DEX-IMP-284-C .ltoreq.1% (a/a) 0.03% 0.05%
0.04% Unspecified .ltoreq.1% each (a/a) 0.922RRT: 0.922RRT:
0.922RRT: impurities 0.12% 0.12% 0.12% 1.057RRT: 1.057RRT:
1.057RRT: 0.08% 0.11% 0.10% 1.184RRT: 1.184RRT: 1.184RRT: 0.34%
0.34% 0.34% Total Impurities .ltoreq.2.5% (a/a) 1.54% 1.57% 1.54%
Water Content Report result 4.2% 5.2% 4.4% Microbial Limits TAMC:
NMT 100 cfu/g <10 cfu/g <10 cfu/g <10 cfu/g TYMC: NMT 10
cfu/g <10 cfu/g <10 cfu/g <10 cfu/g S. aureus: absent in 1
g absent/g absent/g absent/g P. aeruginosa: absent in 1 g absent/g
absent/g absent/g Bile-tolerant gram-negative absent/g absent/g
absent/g bacteria: absent in 1 g Polymorphism Report Form Form 1
Form 1 Form 1 Particle Size: Report results D10 Results: D10
Results: D10 Results: D10 Results (Target: 0.56 .mu.m 0.50 .mu.m
0.51 .mu.m D50 Results D50 ~2 .mu.m D50 Results: D50 Results: D50
Results: D90 Results D90 .ltoreq.5 .mu.m) 2.37 .mu.m 1.97 .mu.m
1.84 .mu.m D90 Results: D90 Results: D90 Results: 5.09 .mu.m 4.68
.mu.m 4.29 .mu.m
FIG. 8 shows XRPD scan at Initial time point.
FIG. 9 shows XRPD scan at 6 Months at 40.degree. C./75RH.
FIG. 10 shows XRPD scan at 12 Months at 25.degree. C./60RH.
EXAMPLES
Preparation of Form 1
3 mL of methanol was added to 300 mg of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) or
alternately 900 ul methanol was added to 100 mg
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) to
form a slurry.
The slurry was temperature cycled between room temperature (RT) and
40.degree. C. (4 hour cycles) for about 6 or 7 days. The sample was
filtered and allowed to dry at ambient followed by about 2 hours
drying under vacuum.
Form 1 has been shown to have suitable characteristics that
justifies its use in a dry powder inhaler (DPI).
Preparation of Form 2
3 mL of acetone:water (20%) was added to 300 mg of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) or
alternately 300 ul acetone:water (20%) was added to 100 mg
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) to
form a slurry. The slurry was temperature cycled between RT and
40.degree. C. (4 hour cycles) for about 6-7 days. The sample was
filtered and allowed to dry at ambient followed by about 2 hours
drying under vacuum.
Preparation of Form 3
2.5 mL of methyl isobutyl ketone (MIBK) was added to 300 mg of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) or
alternately 900 ul of MIBK was added to 100 mg of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) to
form a slurry. The slurry was temperature cycled between RT and
40.degree. C. (4 hour cycles) for about 6-7 days. The sample was
filtered and allowed to dry at ambient followed by about 2-3 hours
drying under vacuum.
Preparation of Form 4
2 mL of 2-propanol was added to 300 mg of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) or
alternately 500 ul of 2-propanol was added to 100 mg
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) to
form a slurry. The slurry was temperature cycled between RT and
40.degree. C. (4 hour cycles) for about 6-7 days. The sample was
filtered and allowed to dry at ambient followed by about 2-3 hours
drying under vacuum.
Preparation of Form 5
2.5 mL of water was added to 300 mg of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) or
alternately 800 ul water was added to 100 mg
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) to
form a slurry. The slurry was temperature cycled between RT and
40.degree. C. (4 hour cycles) for about 6-7 days. The sample was
filtered and allowed to dry at ambient followed by about 2-3 hours
drying under vacuum.
Form 5 can also be prepared by microfluidization to produce
material with a particle size in the respirable range. 10 g of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) was
suspended in 190 g water. The suspension was processed using a
Microfluidics High Pressure Homogenizer equipped with a 200 .mu.m
auxiliary processing module and a 100 .mu.m interaction chamber.
The unit was operated at a pressure of approximately 750 bar. As a
final step, the material was spray dried to isolate the dried Form
5 material.
Form 5 is stable and is particularly suitable for administration by
a nebulizer.
Preparation of Form 6
1 mL of dimethylformamide (DMF) was added to 300 mg of
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) or
alternately 200 ul DMF was added to 100 mg
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sul-
fanediyl-di-.beta.-D-galactopyranoside (e.g. amorphous form) to
form a slurry. The slurry was temperature cycled between RT and
40.degree. C. (4 hour cycles) for about 0.5-1 day. The sample
formed a solution and was allowed to evaporate. The sample was
dried for ca. 2 hours under vacuum. Alternately, once precipitation
of was observed during the evaporation step, the sample was
temperature cycled for a further about 1 day and dried for about 1
day under vacuum.
Preparation of Amorphous
Table 4 provides an example of spray-drying conditions used to
prepare amorphous
3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl-
]-1,1'-sulfanediyl-di-.beta.-D-galactopyranoside. Alternately, the
spray-drying solvent can have other proportions of acetone:water
from 50:50 to 80:20.
TABLE-US-00006 TABLE 4 Spray-Drying Conditions for Amorphous
3,3'-Dideoxy- 3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-
1-yl]-1,1'-sulfanediyl-di-.beta.-D-galactopyranoside (API) Solvent
Acetone:Water (50:50) - 250 mL API 8.0 g Feed Concentration 3.5%
wt/wt Relative saturation of the drying gas 1.4/0.1% at the outlet
of the drying chamber Flowrate of feed to spray dryer 5 ml/min
Rotameter 60 mm Drying gas temperature at inlet to 144.degree. C.
drying chamber Drying gas temperature at outlet 75.degree. C. of
drying chamber Temperature at exit of condenser 5.degree. C. Drying
time 50 min
* * * * *